Cancer vaccines represent a promising immunotherapeutic approach, but thus far have achieved only limited success in the clinic. One of the major challenges to successful cancer immunotherapy is the presence of intrinsic immune inhibitory mechanisms that can dampen induction of effective immunity against tumor-associated self antigens. Knowledge of these immunosuppressive regulators could be exploited therapeutically to improve vaccine efficacy for the treatment of cancer. During studies of scavenger receptor-A (SR-A), a pattern recognition receptor primarily expressed on antigen presenting cells (APCs), our laboratory made an unexpected discovery that lack of SR-A significantly enhanced vaccine-generated immunity against poorly immunogenic tumors. The findings, for the first time, demonstrate that SR-A is able to attenuate immune-adjuvant effects provided by both endogenous and exogenous 'danger' molecules. Furthermore, antigen-presenting cells from SR-A deficient mice, such as dendritic cells (DCs), are more responsive to inflammatory stimuli (e.g., TLR agonists) and display a more potent immunostimulatory capability compared to those from wild-type counterparts. Based on these observations we hypothesize that scavenger receptor-A is a previously unrecognized repressor of antigen-specific immunity. The overall objectives of the proposed research are to understand the immunological and biochemical mechanisms underling the enhanced antitumor response observed in SR- A deficient mice, and to evaluate the feasibility of silencing SR-A as an approach to enhance vaccine efficacy. We plan to test the central hypothesis and accomplish the objective of this proposal by pursuing the following specific aims: 1) Determine the regulatory roles of SR-A in immunological .functions of APCs and antigen-specific adaptive immune responses; 2) Determine the molecular mechanisms by which SR-A modulates Toll-like receptor-mediated signaling in dendritic cells; and 3) Determine the ability of SR-A-silenced dendritic cells to promote an antigen-specific CTL response and long-term antitumor immunity using clinically relevant models. Dissection of the global contribution of SR-A to host immunity or tolerance, and unraveling the molecular details of TLR-mediated inflammatory pathways modulated by this receptor will provide essential information on the role of SR-A in immune homeostatic functions. Further, successful testing of SR-A-silenced dendritic cells as a vaccine to break tolerance against tumor- associated self-antigens will provide a novel immunotherapeutic approach targeting the inhibitory innate receptor. [unreadable] [unreadable] [unreadable]